Presently antiretroviral therapies can preserve or restore immune function in HIV-infected people, but roughly 50% of them succumb to mild sub-dementia forms of HAND that are largely refractory to treatment. We propose innovative research to test the new hypothesis that the pathogenic processes responsible for HAND ensue early after virus transmission, they persist despite later antiviral or immune control of virus, an they may be exacerbated by opiate use. The testable translational implication of this hypothesis is that therapies targeting key determinants of the early neuropathogenesis may prevent HAND. The hypothesis will be tested in an established system of HIV infection and early cognitive impairment in immunocompetent mice inoculated with mouse-tropic HIV, EcoHIV. The natural history of cognitive disease in these mice closely models mild HAND in HIV-infected humans. HIV enters the mouse brain within 5 days of systemic infection with cognitive impairments developing 4-5 weeks later and persisting despite adaptive antiviral immunity and virus suppression. Brain pathology was normal but cognitive dysfunction correlated with suppression of synaptic plasticity genes including CaMKII and SYN2; both genes also had gene-silencing epigenetic modifications of histone 3 on their promoters as determined by chromatin immunoprecipitation, suggesting stable disruption of some synaptic functions in HAND. Chronic morphine exposure and HIV synergized in causing cognitive impairment in mice. We postulate that the brain injury inflicted soon after infection of mice, before establishment of adaptive immune responses, is largely irreversible and initiates a neuropathogenic program leading to cognitive impairment. The overall goals of this application are to test this proposition, explore selected mechanisms involved, and apply the findings to identify therapies to prevent HAND. The Aims are: 1) To define virological and synaptic determinants of subclinical HAND and its progression to clinical disease; 2) To determine morphine effects in subclinical and clinical HAND; 3) To test a novel mechanism of pan- dysregulation of synaptic plasticity genes in murine HAND by chromatin remodeling and the potential role of Tat; 4) To explore interventions disrupting preclinical HAND to prevent progression to clinical disease. We believe that use of cognitive impairment as a relevant disease readout, combined with versatility of mouse experimentation, will facilitate identification of key physiological and molecular processes involved in HAND. Studies will be conducted exclusively in mice, both conventional and specific knock-out strains, principally through systemic infection with EcoHIV, with/without chronic morphine treatment through implantation of timed- release pellets. Selected disease markers identified in mice will be confirmed in archival brain tissues of MND patients stratified by opiate addiction. Timed interventions will include inhibitors of chromatin remodeling.